The β-Globin Dominant Control Region

The strongest evidence for the existence of an important control in the flanking region of the globin gene domain was provided by the analysis of human γβ-thalassaemias.1,2 Patients with heterozygous Dutch γβ-thalassaemia have a deletion that removes 100 kb of DNA, leaving the β-globin gene and the promoter and enhancer regions intact. However, it abolishes expression of the deleted chromosome and leaves the gene in an inactive chromatin configuration.3–5 The wild-type allele on the other chromosome is expressed at normal levels, indicating that there is no shortage of trans-acting factors. This suggests a cis effect on β-globin gene transcription, which could be caused by a loss of positive acting elements or by the juxtaposition of the intact β-globin gene and sequences that remain in an inactive chromatin configuration in erythroid cells. The first indication that positive acting sites may be involved in activation of the β-globin domain came with the observation of erythroid specific DNasel hypersensitive sites that map 6–18 kb upstream from the e-globin gene (Fig. 1).6–8